UA118667C2 - Processes for the preparation of an apoptosis-inducing agent - Google Patents

Abstract

Provided herein is a process for the preparation of an apoptosis-inducing agent (Al), and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the process provided herein. EMBED ISISServer , Al

Description

This application claims priority to prior US patent application No. 61/780621, filed Mar. 13, 2013, and priority to prior patent application

US No. 61/947850, filed Mar. 4, 2014, each of which is incorporated herein by reference in its entirety.

The field of technology to which the invention belongs

The present invention relates to methods of obtaining an apoptosis-inducing agent and chemical intermediates for its preparation. Also, the present invention relates to new chemical intermediates related to the methods envisaged in this context.

Prerequisites for the creation of the invention 4-(4-C2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl|methyl/)piperazin-1-yl)-M-(/3-nitro-4-

1-tetrahydro-2H-pyran-4-ylmethyl)amino|phenylsulfonyl)-2-(1H-pyrrolo|2,3-b|pyridin-5-yloxy)benzamide (hereinafter "compound 1") and 4-(4-ShCh2- (4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl|methyl)piperazin-1-yl)-M-(3-nitro-4-(1B,4H8)-(4-hydroxy- All -2, which have, among other things, antitumor activity as agents causing apoptosis.

Compound 1 has the formula nm zhi y y

Ah I MO what. she ШЧ di ryk shi v y What is, -i ie m she i: ha i; : hi NU; Since the day of the rda

Se p

Compound 2 has the formula: nm a

No and M and; and and | Mo, no o chi she 7x nu im i tuyun y U KE Hey Z Ne, reis s (Z i I

Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. US Patent Publication No. 2010/0305122 discloses Compound 1, Compound 2, and other compounds that effectively bind to the All-2 family protein, and pharmaceutically acceptable salts thereof. In patent publications

US Nos. 2012/0108590 and 2012/0277210 disclose pharmaceutical compositions that contain such compounds and methods of treating neoplastic, immune, or autoimmune diseases that include such compounds. US Patent Publication No. 2012/0129853 discloses methods of treating systemic lupus erythematosus, lupus nephritis, or Sjogren's syndrome that include the following compounds. US Patent Publication No. 2012/0157470 discloses

Pharmaceutically acceptable salts and crystalline forms of Compound 1. Disclosure of US Patent MoMo 2010/0305122; 2012/0108590; 2012/0129853; 2012/0157470 and 2012/0277210 are hereby incorporated by reference in their entirety.

Brief summary of the essence of the invention

This invention relates to methods of obtaining compounds of formula A1:

Not m"

BO NYA ro -000 M u u: 0: ge. y dich she NI an SHA den « b u ny kat them u

NO mice

SI TAIH

UlLLchiLY; ik o. ЧК ра да В? choose from: -f t

Also, this invention relates to compounds of the formulas: nm z, - i and M» rak aku

Her and sho di eh ni Ok, nene zhen pi / K.; and E and K. sq. g

Tsi A Y M ( U KOL shchi TOZ t M ; Y

Bg and (OY) where B means C:-C:2-alkyl; and methods of their preparation.

Detailed description of the invention

The present invention relates to a method of obtaining compounds of the formula A: nm», M ich

Zh chan y oon OMOY en NIK a SY Me YN. Inv ey z shchei She s TAT kih ia

Where B2 is chosen from: A | " which includes: (a) combining a compound of formula (K):

To: but I'm a Goth

Her che i uch seni t Mov i zh o ke g chk

Ku do" o some (0. where B means C1-C2-alkyl,

with tert-butoxide, an aprotic organic solvent and water, to obtain the compound of formula (I): ho esche koe i Ho shi; and MM still

The next day - in the combination of the compound of the formula with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EBAS), 4-dimethylaminopyridine (OMAR), an organic solvent and or with the compound of the formula (M), to obtain the compound of formula (AT), where

BU

7 Zh

IN? means:

Mo. shh

ZK wes osa pe t

S. and I

Mne Ko, Shche Y

OO) or with a compound of formula (P), to obtain a compound of formula (Ai), where B? means: ha .

MO" about Ya

Nam-3- UM (Tuvn mya lany Those her daughters

And also her ( g I! : thus obtaining the compound of the formula (A1).

OAZHA k

In one embodiment, V? means: I would AN shchi Kh

In another embodiment, V? means: hey

In some embodiments, A is C1-C6-alkyl. In some embodiments, A is C--C--alkyl. In some embodiments, AB is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and neobutyl. In some embodiments, PE is tert-butyl.

In one embodiment, the method contemplated herein further comprises: (c") combining a compound of formula (M)

MO" gu 9 223

Mn; (M)

with a base in the form of a tertiary amine, an organic solvent and either (tetrahydro-2H-pyran-4-ylylmethanamine or its salt, to obtain a compound of formula (M), or with (18,48)-4-(aminomethyl)-1-methylcyclohexanol or its salt, to obtain the compound of formula (P).

In one embodiment, the salt of (18,4H8)-4-(aminomethyl)-1-methylcyclohexanol, from stage (c"), is a salt of p-toluenesulfonic acid.

In another embodiment, the method contemplated herein further comprises: (4) combining a compound of formula (0):

SO re KAH, moe ne t GT U

Qui hek ai G5-. My book

BG (Z where A means C:1-C:2-alkyl, with the compound of formula (1): i.

M shin schelenykh still si (V. 10 . . . | SHІ . . .) with a source of palladium, tert-butoxide and with a phosphine ligand, in an aprotic organic solvent, to obtain the compound of formula (K).

In some embodiments, the phosphine ligand is a compound of formula (U): p st

eat what

I

MMe" (V.

In other embodiments, the phosphine ligand is selected from the group consisting of 3:

IZ -K. Be KASHI Ve A . ve y " to y roya - pe, I -- oh FO I ! ЖЙ же

KK Oz; , KO

In another embodiment, the method contemplated herein further comprises: (e) combining a compound of formula (B) with a compound of formula (C):

Her -

BUT sl p p» Y

SHM and I (В Вб where В means C1-C12-alkyl, and with tert-butoxide, in an organic solvent, to obtain the compound of formula (0).

In another embodiment, the method contemplated herein further comprises: () combining a compound of formula (A) ! Art

VE GA with V'MaH, in an aprotic organic solvent; where V! means C1-C6-alkyl; and X means SI, Vg or I; and (9) combining C1-C12-alkyl chloroformate or di(C1-C12-alkyl dicarbonate) with the product from step (I) to obtain a compound of formula (C).

In another embodiment, the method provided in this context further comprises: (n) combining a compound of formula (E) 1 and 2 with DMF and ROS to obtain a compound of formula (PE)

The procedure for combining the compound of formula (ER) with a source of palladium and 4-chlorophenylboronic acid, in an organic solvent, to obtain the compound of formula (C):

Co

KE pek, - y y di sm same dev ok same.

Seya (0); () combining the compound of formula (C) with BOC-piperazine and sodium triacetoxyborohydride, in an organic solvent, to obtain the compound of formula (H): bos tA

ТЯ у и ма TE and (K) combining the compound of formula (Н) with hydrochloric acid, to obtain the compound of formula ().

In one embodiment, the method includes stage (a), stage (p"), stage (c") and stage (4). In one embodiment, the method includes stage (a), stage (B"), stage (c"), stage (4) and stage (e). In one embodiment, the method includes stage (a), stage (B"), stage (c"), stage (4), stage (e), stage (5) and stage (4). In another embodiment, the method includes stage (a), stage (B"), stage (c"), stage (9), stage (e), stage (i), stage (9), stage (GP), stage ( i), stage (|) and stage (K).

In one embodiment, the method includes steps (a), (6") and (4). In another embodiment, the method includes steps (a), (67), (4) and (e). In another embodiment, the method includes steps (a), (67), (a), (M), (), () and "K). In another embodiment, the method includes steps (a), (67), (c"), (a), (M), (i), 0) and "K). In another embodiment, the method includes steps (a), (6"), (a), (M), (9), (P), (I), () and "K). In another embodiment, the method includes steps (a), (6"), (9), (e), (0), (9), (n), (0), F) 1 (K).

Also, this invention relates to a method of obtaining Compound 1 of the formula: no 5,

AND; y M y y and check what"

In Vo i 7 an ry vi shk -MNO it y x Kn pt Z - ( I shnih o d ud sh (0)

Koo) 7 which includes: (a) combining a compound of formula (K):

SO koche

Her Sho ti tr U to a M schy M

M et al

It is possible to use six more compounds that are MH and where B means Si1-Si2-alkyl, with tert-butoxide, an aprotic organic solvent and water, to obtain the compound of formula (I):

Y Mo Y in U and Sh

N and i

And on and or me

I

I: MI k (r) combining the compound of formula (I) with the compound of formula (M)

MO N er yaz

The mixture was purified with (M) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EBAS), 4-dimethylaminopyridine (OMAR) and an organic solvent to obtain the compound of formula (1).

In some embodiments, A is C1-C6-alkyl. In some embodiments, A is C--C--alkyl. In some embodiments, AB is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and neobutyl. In some embodiments, PE is tert-butyl.

In one embodiment, the method for preparing Compound 1 further includes: (c) combining a compound of formula (M) with

And we are about the dishes

Mne (Mi) with (tetrahydro-2H-pyran-4-yl)umethanamine, a base in the form of a tertiary amine and an organic solvent, to obtain the compound of formula (M).

In another embodiment, the method for preparing Compound 1 further comprises: (4) combining a compound of formula (0):

SOL

This is Sur

Her her Y a - Zm 7

BE (2) And where A means C:1-C:2-alkyl, with the compound of formula (1):

N s schu ne nm kn

(V.) with a source of palladium, tert-butoxide and a phosphine ligand, in an aprotic organic solvent, to obtain the compound of formula (K).

In some embodiments, the phosphine ligand is a compound of formula (U): i.

SA

TT.

In other embodiments, the phosphine ligand is selected from the group consisting of:

F Zh Ke 4. "j A. ge i

And them - a song by S

VC; with » | x y

In another embodiment, the method for preparing Compound 1 further comprises: (i) combining a compound of formula (B) with a compound of formula (C):

Co

BUT. sna s t (I

And h

MM, we

HB) Wes where B means C1-C12-alkyl, and with tert-butoxide, in an organic solvent, to obtain the compound of formula (0).

In another embodiment, the method of obtaining Compound 1 further includes: () combining a compound of formula (A)

And you and Sh

Be (Az with B'MOX, in an aprotic organic solvent; where B! means C.i.i.-Ci-alkyl; and X means CI, Bg or I; and (9) combining C1-C12-alkyl chloroformate or di(C1-Ci2 -alkyl udicarbonate with the product from stage (I), to obtain the compound of formula (C).

In another embodiment, the method of obtaining Compound 1 further includes: (n) combining a compound of formula (E)

ev : ry ok v with DMF and ROSI", to obtain the compound of formula (B): oh wow!

AND; and si (vu () combining the compound of the formula (B) with a source of palladium and 4-chlorophenylboronic acid, in an organic solvent, to obtain the compound of the formula (C): a and di i vyh a schi; () combining the compound of the formula (C) with BOC-piperazine and sodium triacetoxyborohydride, in an organic solvent, to obtain the compound of the formula (H):

Vos g p fe

Add (NO and (K)) the combination of the compound of the formula (H) with hydrochloric acid to obtain the compound of the formula ().

In one embodiment, the method for preparing Compound 1 includes steps (a)-(4). In one embodiment, the method for preparing Compound 1 includes steps (a)-(e). In another embodiment, the method for preparing Compound 1 includes steps (a)-(4). In another embodiment, the method for preparing Compound 1 includes steps (a)-(K).

In one embodiment, the method for preparing Compound 1 includes steps (a), (b) and (4). In another embodiment, the method of preparing Compound 1 includes steps (a), (b), (c) and (e). In another embodiment, the method of obtaining

Compound 1 includes stages (a), (B), (9), (M), (I), (0) and "K). In another embodiment, the method of obtaining Compound 1 includes stages (a), (B), (c), (4), (M), (i), (0) and "K). In another embodiment, the method of obtaining Compound 1 includes stages (a), (B), (9), (Y), (9), (M), (I), (0) and "K). In another embodiment, the method of obtaining Compound 1 includes stages (a), (B), (a), (e), (0), (9), (n), (0), 0) 1 (K).

Also, this invention relates to the method of obtaining Compound 2 of the formula: no y M y rak x. HO M a g i KN i ykhiu i i CHI ; same tya i- NM U-pl

ACTS" and U sh, - and 7 o y

C 21, which includes: (a) combining a compound of formula (K):

Ov in AU, aw more

NOT in the spirit of x

HE what and she "M nn rah still and in

Ж ХК blue 0 where B means Si1-Si2-alkyl, with tert-butoxide, an aprotic organic solvent and water, to obtain the compound of formula (I):

BO in Z, o ni du yar, still a x Shchy M

M n sh i va

C " also si (2; (p) combining the compound of formula (I) with the compound of formula (P) ih MO» non b-Kd-mv ton o whose (P and C 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EBAC), 4-dimethylaminopyridine (OMAR) and an organic solvent to obtain a compound of formula (2). 10 In some embodiments, A is C1-C8-alkyl. In some embodiments, A is C--C--alkyl. In some embodiments, AB is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and neobutyl.In some embodiments, PE is tert-butyl.

In one embodiment, the method for preparing Compound 2 further comprises: (c) combining a compound of formula (M)

MO" which 9) where

MN"; (M) with (18,48)-4-(aminomethyl)-1-methylcyclohexanol or its salt, a base in the form of a tertiary amine and an organic solvent, to obtain the compound of formula (P).

In one embodiment, the salt of (1H8,48)-4-(aminomethyl)-1-methylcyclohexanol from stage (c) is a salt of p-toluenesulfonic acid.

In some embodiments, the process for preparing Compound 2 further comprises step (a) as described above for preparing Compound 1.

In some embodiments, the method for preparing Compound 2 further comprises step (e) as described above for preparing Compound 1.

In some embodiments, the method for preparing Compound 2 further includes step (It) and step (4) as described above for preparing Compound 1.

In some embodiments, the method of obtaining Compound 2 further includes stage (GP), stage (i), stage (I) and stage "K") as described above for the preparation of Compound 1.

In one embodiment, the method for preparing Compound 2 includes step (a), step (B), step (c) and step (4). In one embodiment, the method for preparing Compound 2 includes step (a), step (B), step (c), step (4) and step (e). In one embodiment, the method of obtaining Compound 2 includes stage (a), stage (Br), stage (c), stage (4), stage (e), stage (i) and stage (9). In another embodiment, the method for preparing Compound 2 includes stage (a), stage (2), stage (c), stage (4), stage (e), stage (7), stage (4), stage (GP), stage (i), stage (|) and stage (K).

In one embodiment, the process for preparing Compound 2 includes steps (a), (6), and (94). In another embodiment, the method for preparing Compound 2 includes steps (a), (6), (4) and (e). In another embodiment, the method of obtaining Compound 2 includes stages (a), (B), (9), (M), (I), (0) and (K). In another embodiment, the method of obtaining Compound 2 includes stages (a), (B), (c), (a), (M), (i), () and "K). In another embodiment, the method of obtaining Compound 2 includes stages (a), (B), (9), (Y), (9), (M), (I), (0) and (K). In another embodiment, the method of obtaining Compound 2 includes stages (a), (6), (a), (e), (7), (9), (P), 0), 0) 1 "(K).

In some embodiments, in step (a), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (a), tert-butoxide is sodium tert-butoxide. In some embodiments, in step (a), the tert-butoxide is potassium tert-butoxide.

In some embodiments, in step (a), the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (a), the aprotic organic solvent is 2-methyltetrahydrofuran.

In some embodiments, in stage (B), stage (2) and/or stage (B5"), the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether , diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, at stage (B), stage (2) and/or stage (B" ), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-

From methyltetrahydrofuran and their mixtures. In some embodiments, in stage (B), stage (2) and/or stage (B"), the organic solvent is dichloromethane.

In some embodiments, in step (c), step (c) and/or step (c"), the base in the form of a tertiary amine is M,M-diisopropylethylamine.

In some embodiments, in step (c), step (c) and/or step (c"), the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether , diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, at stage (c), stage (c) and/or stage (c" ), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, in stage (c), stage (c) and/or stage (c"), the organic solvent is acetonitrile.

In some embodiments, in step (4), the compound of formula (I) is first combined with a base, prior to combining in step (4). In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is selected from the group consisting of KzROx, MazROz, Maon, Con, CoCOz, or MagSoz. In some embodiments, the basis is KzRO»4. In some embodiments, in step (4), the compound of formula (I) first

BO is combined with the base, in one or more solvents, prior to combining in step (4).

In some embodiments, in step (4), the palladium source is Ra»draz or

Kcinnamil)Rasi|;». In some embodiments, in step (a), the palladium source is Raghavaz.

In some embodiments, in step (4), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

In some embodiments, in step (4), the tert-butoxide is anhydrous. In some embodiments, in step (a), the tert-butoxide is anhydrous sodium tert-butoxide.

In some embodiments, in step (4), the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2 -butanone, dichloromethane, chloroform, carbon tetrachloride 60, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid,

acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, in step (4), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (4), the aprotic organic solvent is a mixture of THF and toluene.

In some embodiments, step (a) further includes the following steps: (1) combining tert-butoxide with a compound of formula (I) in an aprotic organic solvent; (2) combining a palladium source, a compound of formula ()) and a compound of formula (0) in an aprotic organic solvent; and (3) adding the mixture from step (1) to the mixture from step (2).

In some embodiments, in step (4), the mixture obtained in step (2) is filtered to step (3).

In some embodiments, step (a) is carried out in an atmosphere of nitrogen or argon.

In some embodiments, in step (4), the catalytic amount of the palladium source is used according to the amount of the compound of formula (I). In some embodiments, the palladium source is

Ragavahz, and the catalytic amount of Ragaraz ranges from approximately 0.5 to 95 mol. to about 2 95 mol. In one embodiment, the catalytic amount of Ragabraz is about 0.75 95 mol.

In some embodiments, in step (4), the catalytic amount of the compound of formula (y) is used according to the amount of the compound of formula (I). In some embodiments, the catalytic amount of the compound of formula ()) is from about 195 mol. to approximately 595 mol. In one embodiment, the catalytic amount of the compound of formula (U) is from about 1 to 95 mol. to about 4 95 mol. In one embodiment, the catalytic amount of the compound of formula (/) is from about 2 to 95 mol. to about 4 95 mol. In one embodiment, the catalytic amount of the compound of formula (U) is from about 1 to 95 mol. to about 2 95 mol. In one embodiment, the catalytic amount of the compound of formula (/) is from about 1 95 mol. to about 2 95 mol.

In some embodiments, in step (e), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (e), tert-butoxide is sodium tert-butoxide. In some embodiments, in step (e), the tert-butoxide is a tert-

Co) potassium butoxide.

In some embodiments, in step (e), the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2 -butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE , benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, in step (e), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (is), the organic solvent is DMF.

In some embodiments, in step (), B' means C:1-C6-alkyl. In some embodiments, B' is isopropyl.

In some embodiments, in step (1), B is methyl and C1-C1-alkyl chloroformate is methyl chloroformate. In some embodiments, B is ethyl and C1-C2-alkyl chloroformate is ethyl chloroformate. In some embodiments, A is tert-butyl and di(C1i-C12-alkyl dicarbonate) is di-tert-butyl dicarbonate.

In some embodiments, at stage (), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (i), the aprotic organic solvent is THF.

In some embodiments, in step (i), the palladium source is Pa(OAc)."

In some embodiments, in step (i), the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2 -butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE , benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, in step (), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMPA,

dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, in step (i), the organic solvent is acetonitrile.

In some embodiments, step (i) includes combining tetrabutylammonium bromide with a compound of formula (ER), a palladium source, and 4-chlorophenylboronic acid in an organic solvent.

In some embodiments, in step (i), the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2 -butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE , benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, in step (|), the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMR, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in stage (I), the organic solvent is a mixture of THF and toluene. In some embodiments, a mixture of

THF and toluene is approximately 1:1 by volume.

In some embodiments, step (|) further includes obtaining a compound of formula (H) as a crystalline solid. In some embodiments, step (|) further includes: (1) adding an aqueous solution to the mixture from step (|), to obtain the aqueous and organic phases; (2) separation of the organic phase from the mixture from stage (1); (3) concentration of the organic phase; and (4) adding an organic solvent to the mixture from step (3) to obtain a compound of formula (H) as a crystalline solid.

In some embodiments of step (4) of step (|), the organic solvent is acetonitrile. In some embodiments of step (4) of step (), the organic solvent is acetonitrile and the mixture is heated to a temperature of approximately 80 "C.

In some embodiments, step (4) of step ()) further includes cooling the mixture to a temperature of from about 10 "C to about -10 "C. In some embodiments, step (4) of step (|) further includes cooling the mixture to a temperature of about -10 "C and isolating the compound of formula (H) as a crystalline solid by filtering the mixture.

In some embodiments, the combination in step (K) is carried out in an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform , carbon tetrachloride, 1,2-dichloroethane,

THF, DMF. NMPA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, the organic solvent is isopropanol.

In some embodiments, step (K) further comprises obtaining the compound of formula (I) as a crystalline solid. In some embodiments, the combination in step (K) is carried out in an organic solvent, and step (K) further includes isolating the compound of formula (I) as a crystalline solid by filtering the mixture.

In some embodiments, the combination in step (K) is carried out in an organic solvent, and step (K) further includes cooling the mixture to a temperature of from about 10°C to about -10°C, until the compound of formula (I) is obtained as a crystalline solid. .

In some embodiments, the combination in step (K) is carried out in isopropanol, and step (K) further includes cooling the mixture to a temperature of from about 10 "C to about -10 "C, until the compound of formula (I) is obtained as a crystalline solid. In some embodiments, the combination in step (K) is carried out in isopropanol, and step (K) further comprises cooling the mixture to a temperature of about -5°C to obtain the compound of formula (I) as a crystalline solid, and isolating the compound of formula (I ) in the form of a crystalline solid by filtering the mixture.

Also, this invention relates to a method of obtaining a compound of formula (C):

SO, sir, I am

Ion

Vb where B means C.1-Ci2-alkyl, which includes: (a) combining a compound of formula (A)

And a ram

K rn o,

Bi (A with B'MaX, in an aprotic organic solvent; where B' means Ci-Cv-alkyl; and X means CI,

Vg or I; and (p) combining C1-C12-alkyl chloroformate or di(C1-C12-alkyl dicarbonate) with the product from step (a) to obtain a compound of formula (C).

In some embodiments, A is C1-C6-alkyl. In some embodiments, A is C--C--alkyl. In some embodiments, AB is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and neobutyl. In some embodiments, PE is tert-butyl.

In some embodiments, B' is C-C-alkyl. In some embodiments, B" is isopropyl.

In some embodiments of the method for preparing the compound of formula (C), the organic solvent in step (a) is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol , tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMRA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, the organic solvent in step (a) is THF.

In one embodiment, B is C1-C6-alkyl.

In one embodiment, A is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and neobutyl.

In one embodiment, A is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and neobutyl; and B' means isopropyl.

In one embodiment, A is tert-butyl and B' is isopropyl.

In some embodiments of the method of obtaining a compound of formula (C), at stage (p), B means methyl and

C1-Ci2:-alkyl chloroformate is methyl chloroformate. In some embodiments, AB is ethyl and

C1-Ci2:-alkyl chloroformate is ethyl chloroformate. In some embodiments, A is tert-butyl and di(C1-C112-alkyl dicarbonate) is di-tert-butyl dicarbonate.

Also, this invention relates to a method of obtaining a compound of formula (0): codes cc

From z-d more

Ve (Z

Co) where B means C1-C12-alkyl, which includes: (x) combining a compound of formula (B)

BUT. Sen

That's it

MM. (B) with the compound of formula (C) ok gai xx KE

This is it

B B (su and tert-butoxide, in an organic solvent, to obtain the compound of formula (0).

In one embodiment, B is tert-butyl.

In some embodiments, the method for preparing a compound of formula (0) further comprises steps (x) and (0): (x) combining a compound of formula (A)

and

AND

Vb (A) with V'MaH, in an aprotic organic solvent; where B' means Ci-Cv-alkyl; and X stands for SI,

Vg or I; (x) combining C1-C12-alkyl chloroformate or di(C1-C12-alkyl)udicarbonate with the product from step (x) to obtain a compound of formula (C).

In some embodiments, in step (x), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

In some embodiments, the organic solvent, in step (x), is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, NMPA, MMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, the organic solvent in step (x) is DMF.

In some embodiments, in step (x), B' means C--C-alkyl. In some embodiments, "FW" means isopropyl.

In some embodiments, in step (x"), the C1-C1-alkyl chloroformate is methyl chloroformate.

In some embodiments, the C1-C6 alkyl chloroformate is ethyl chloroformate. In some embodiments, the di(C1-C12-alkyl dicarbonate is di-tert-butyl dicarbonate.

In some embodiments, in step (x1), the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (x), the aprotic organic solvent is THF.

Also, this invention relates to the compound of formula (3): nm y

U. Mi

LSH that

I am

ROOF 9 her uk m M- U. owls. 5 U che Mjohya si !

In one embodiment, the compound of formula (3) is prepared by the following steps: (y) combining the compound of formula (B)

N br of "MM Sh

I (B) with a compound of formula (C): so se -KE

And eat

VO

Where AB means tert-butyl, and tert-butoxide, in an organic solvent, to obtain the compound of formula (0):

SO re

Wasp

Mne kn shcha tu y.

Ve (2)

where B means tert-butyl; and (27) combining a compound of formula (0) where AB is tert-butyl; with the compound of formula (1):

N g cr v

M NS o» sia (0). source of palladium, tert-butoxide and a phosphine ligand, in an aprotic organic solvent.

In one embodiment, the phosphine ligand in step (7) is a compound of formula (U): a | with

I grew up with them

WITH

92 (5.

In other embodiments, the phosphine ligand is selected from the group consisting of:

ZD M ozh» us Vk v j e Yi shli r-va wa sche ik) - Ka A. May - Be ra i fun " -rv SI kov, I shk

VK." "? PC

In one embodiment, in stage (7), the palladium source is Ragaraz.

In some embodiments, in step (7), the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, MMP, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the aprotic organic solvent is a mixture of THF and toluene.

In some embodiments, in step (7), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

In some embodiments, in step (7), the tert-butoxide is anhydrous sodium tert-butoxide or anhydrous potassium tert-butoxide.

In some embodiments, step (7) further includes the following steps: (1) combining tert-butoxide with a compound of formula (I) in an aprotic organic solvent; (2) combining a palladium source, a compound of formula ()) and a compound of formula (0) in an aprotic organic solvent; and (3) adding the mixture from step (1) to the mixture from step (2).

In some embodiments, in step (7), the mixture obtained in step (2) is filtered to step (3).

In some embodiments, step (7) is carried out in an atmosphere of nitrogen or argon gas.

In some embodiments, in step (7), the catalytic amount of the palladium source is used according to the amount of the compound of formula (I). In some embodiments, the palladium source is

Ragavahz, and the catalytic amount of Ragaraz ranges from approximately 0.5 to 95 mol. to about 2 95 mol. In one embodiment, the catalytic amount of Ragdraz is about 0.75 95 mol.

In some embodiments, when the phosphine ligand in step (7) is a compound of formula (.)), the catalytic amount of the compound of formula ()) is used according to the amount of the compound of formula (I). In some embodiments, the catalytic amount of the compound of formula (U) is from about 1 95 mol. to about 5 95 mol. In one embodiment, the catalytic amount of the compound of formula ()) is from about 195 mol. to approximately 495 mol. In one embodiment, the catalytic amount of the compound of formula (U) is from about 2 to 95 mol. to about 4 95 mol. In one embodiment, the catalytic amount of the compound of formula (/)) is from about 1 95 mol. to about 2 95 mol. In one embodiment, the catalytic amount of the compound of formula (U) is from about 1 to 95 mol. to about 2 95 mol.

In another embodiment, the present invention relates to compounds of the formulas: not and: Yes

Owls "( / still more or IK IH a

With no M same or inv same She dl

Ve I S

In some embodiments, the methods described herein are improved methods for chemically preparing Compound 1 or Compound 2 on a commercial scale. Without being bound by a particular theory or mechanism of action, the methods described herein significantly improve the overall efficiency and product yield, Compound 1 or Compound 2. Prior methods (eg, US Patent Publication Nos. 2010/0305122 and 2012/0157470 and Publication

International patent applications under the numbers UMO 2011/15096 and MO 2012/071336) were found to be insufficiently suitable for obtaining Compound 1 on a commercial scale. Thus, the methods provided in this context represent improved methods of synthesizing compounds in quantities required for clinical and/or commercial scale-up. Improvements over these prior methods include, but are not limited to, overall yield of Compound 1 or

Compounds 2, overall method efficiency and economics, mild reaction conditions, practical isolation/purification methods, and "viability" for commercialization.

An improved method contemplated in this context involves a selective nucleophilic aromatic substitution reaction ("ZpAg reaction") of compounds (B) and (C), which can be carried out under mild conditions, during a shorter reaction time when compared to previously described methods , as disclosed, for example, in US Patent Publication Nos. 2010/0305122 and 2012/0157470 and in International Patent Application Publication Nos. MO 2011/15096 and MO 2012/071336. Without being bound by theory, the improved 5 pAg reaction of compounds (B) and (C) does not cause the formation of regioisomeric by-products, necessitating further purification to remove the by-products, as is the case in the previously described methods. The 5pAg reaction in the previous methods also requires a longer reaction time and harsh reaction conditions, which, as a result, leads to a decrease in overall yield compared to the methods described in this context. In addition, the previous methods also require time-consuming purification from intermediate products, which is not possible in the method

Co.) of large, commercial scale. The methods described in this context are more convergent than the previous methods, resulting in a highly efficient cross-linking reaction of compound (0) and as a free base of compound (I) in high yield. In some embodiments, in the case of the methods described in this context, crystalline solid intermediates (H) and (I) are used, which allow effective purification by crystallization to remove impurities - advantages not available in the previously described methods.

The following diagrams illustrate one or more embodiments of the method contemplated herein. In some embodiments, a compound of formula (0) is prepared from compound (B) and compound (C) as shown in Scheme 1 below. A compound of formula (B) can be prepared by methods known in the art, for example as shown in International application number MO 2000/047212 and in U. At. Spent 5os., 1959, 81:743-747. A compound of formula (C) can be prepared using methods known in the art, for example, as shown in International Application No. MO 2006/059801 and Tempaneadgop Ieyege, 2008, 49(12), 2034-2037; or as shown in

Schemes 2.

Scheme 1 pov sp K poru u s soy o. we De uche

And mon vvvvnny and ziya h

In KO / DMF In "

The compound of formula (C) shown in Scheme 1 can be prepared from the commercially available compound (A) as shown in Scheme 2 below, where "B'MouX" represents the Grignard reagent, where B! means an alkyl group and X means SI, Vg or I. Electrophilic acetylating reagent, na

Scheme 2, may be, but not limited to, methyl chloroformate or ethyl chloroformate or BOC2O.

Scheme 2 4 gzikinZ

Av-E 2. Electrophilic acetylating reagent p-E

HER pnnnnnnnnvdnnnnnppnTnyshishny 5.

Yi Kos

This is it

And E

A typical reaction according to Scheme 2 is presented below. 1. 1RUMaV: Sov shk 75. Voso re -E t EE g Vg

In another embodiment, a compound of formula (I) is prepared from compound (E) as shown in Scheme 3 below. Compound (E) is commercially available or can be prepared by methods known in the art, for example as shown in U.S. Pat. under the number 3813443 and in Rgoseedipd5 oi She Spetisai! Bossiviu, Gopaop, 1907, 22, 302.

Scheme Z y k Vos Bos CE sn GU Eh ; - M a nam V. i i Y I TE. ill. and Zn 27 AMeRA. ROS sy sim A NM topus Mona kshi sub, pronvnvnnnnnn GK yo i "Honnnnthchchnnniayu i SCHI sennia S a kn dyh y - veOAsv SK Her ryy che

E in masses and Sr. Zh

Ge se ge so IZ

In another embodiment, a compound of formula (M) is prepared from compound (M) as shown in Scheme 4 below. Compound (M) is commercially available or can be prepared by methods known in the art, for example as shown in WO 585940 and at 9. At.

Spent 5os., 1950, 72, 1215-1218.

Scheme 4

NM.

MO that To" n

KOZH Mesm, oiBA opti M

With C Her Op rea san de Vaux To se8 still m: But in h

M n and M kh i (3 -7

M

In another embodiment, a compound of formula (P) is prepared from compound (M) as shown in Scheme 4 below.

Scheme 4 9 no, MO, and CsNzMO, no,

SsnamMaVg u ne ra Topuol, OSS re and Talubl or ry shcha kali i oso Fo-zos oo a pam 1

Se ich; OHM

Co. RSuz

With IS Uz e Kt t. / With no. but.

RE I 1) KaMi. wet 7 There is a Cretori and TIF catalyst (called zezzhkhnzhntnyatk хх ктичккий В и осм. Зо В! 2)mmMmesM/rtBA Y

Auggie TVA No g VO;

But, and MO" MO"! In r ne mesk, TEH Х ше ко S mon snd Y mno ih he fr | A; en (4 z tr Ous Vo s io h ra rtzA NA We: m r

In another embodiment, a compound of formula (1) is prepared from compound (0) and compound (I) as shown in Scheme 5 below. Compound ()) can be prepared by methods known in the art, for example as shown in International Appl. for the patent under number U/O 2009/117626 and v

Ogdapoteizaiisv, 2008, 27(21), 5605-5611.

Scheme 5 sOkhV dos ol HM,

Not M

Xia Goa M se to! ! still A doty tut tt b in (y ie r. gg na she Kovi -eooyuuyem z - shM 7 n I ne KI YAM, nn em n mmez y r. sspova that, y

M rogi i Kk vi MK. Mr. Razivats, SNY series t Z,

In manure sl He 7 I h : . And there's more in this book!

MO" schi ve in

About Her 1

Her and t hu still kova sut ban S

A S MO" N r o

T, " "SHY -Zhras.omAv.. | from the hert to her Z rea ana SNS and Y koni o - I and o

Saekh oyu - what) and why

AI is not the same as DZ

AND

Heart

In another embodiment, the compound of formula (2) is prepared from compound (I) and compound (P) as shown in the accompanying Scheme 6, wherein the preparation of compound (P) is carried out as shown in Scheme 4 and the preparation of compound (I) is carried out as shown in Scheme 5.

Scheme 6

Mo. "7 deky YN sosen - let tr ko Ne y shk so Kiya - eV t . May y 15 in Pam bonii zim Nam . a y ! n OO y V A oh b I KE EVAS, VMAK vy 4 y o Ki Sveyuieot EN yn

Zsch ho not her their rya od shk ma o leon a oo A I ! ver and dia

Tk v Miz sit EY and them

With Mt i and du

In some embodiments, the preparation of a compound of formula (K) from compound (0) and compound (I) is carried out in air and/or under humidity sensitive conditions, and further the preparation is carried out in an inert atmosphere, for example using nitrogen or argon gas .

Without being bound by any particular theory, the use of compound (0) as an intermediate in the preparation of a compound of formula (1) and a compound of formula (2), as shown in the above Schemes 1-6, represents an improvement over previously described methods for preparing compounds of formula (1) and compounds of formula (2). In some embodiments, improvements include higher product yields, shorter reaction times. In some embodiments, improvements are provided when B is tert-butyl in compound (0).

Schemes 1-6 are non-limiting examples of the method provided in this context. Solvents and/or reagents are known compounds and may be used interchangeably within the skill of one skilled in the art.

Abbreviations used in Schemes 1-6 mean the following:

Yara 111110

Unless otherwise indicated, the temperatures at which the reactions according to Schemes 1-b are carried out are not critical. In some embodiments, when a reaction temperature is specified, this temperature can be varied from about plus to minus, 0.1 "C, 0.57, 1.57C, or 10C. Depending on which solvent is used in a particular reaction, the optimal temperature can be varied In some embodiments, the reactions are carried out in the presence of vigorous stirring sufficient to maintain a substantially homogeneous dispersed mixture of reactants.

In carrying out the reaction contemplated in this context, neither the rate nor the order of addition of reagents is critical, except as otherwise indicated. Unless otherwise specified, reactions are carried out at atmospheric pressure. Except as otherwise indicated, the exact amount of reagents is not critical. In some embodiments, the amount of reagent can be varied by about 10 95 mol. or approximately 10 95 wt.

Except as otherwise indicated, the organic solvents used in the case of the methods provided in this context can be selected from those commercially available or otherwise known to one skilled in the art. Suitable solvents for this reaction are within the skill of the skilled artisan and include solvent mixtures. Examples of organic solvents contemplated for use herein include, but are not limited to: pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2- butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), hexamethylphosphoramide (NMPA), M-methyl-2-pyrrolidinone (MMP), nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran and their mixtures.

In some embodiments, the organic solvent used in the methods provided herein is an aprotic organic solvent. As intended in this context, an aprotic solvent is a solvent that does not contain an acidic hydrogen atom or a hydrogen atom capable of forming a hydrogen bond (eg, not

Zo is bound to an oxygen atom or a nitrogen atom). The aprotic organic solvent can be selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF,

DMF, MMR, NMRA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran and their mixtures. In some embodiments, the aprotic organic solvent is THF. In some embodiments, the aprotic organic solvent is DMF. In some embodiments, the aprotic organic solvent is acetonitrile.

As used herein, the term "tertiary amine base" refers to an amine substituted with three alkyl groups, such as triethylamine or M,M-diisopropylethylamine.

As intended in this context, the term "catalytic amount" refers to less than one molar equivalent of a reactant or reactant in a given reaction as set relative to another reactant or reactant in the reaction mixture. In some embodiments, the catalytic amount is determined as a molar percentage relative to the other reactant or reactant in the reaction mixture.

As intended in this context, the term "palladium source" refers to a source of palladium in a stable oxidation state, i.e. Pa(o), Pa(I), RI!) and/or RAM). Palladium may be a free metal, such as in powder form, or may be bound to one or more ligands, such as Rasi, Ragabaz, Rasi(PPH3)»2, RY(RR3)», RY(OAs)» : or (cinnamyl)Resi|».

As intended in this context, the term "phosphine ligand" refers to a compound of formula RAZ, wherein each B' is independently selected from C1-C6-alkyl or phenyl, wherein the aryl group is optionally substituted with C1-C6-alkyl, phenyl, trialkylamino , alkoxy or halogen.

As intended in this context, unless otherwise defined, the term "about" means that the value or quantity to which it relates may vary by 5 95, 2 95, or 1 95.

The products obtained by any method contemplated herein may be isolated by standard methods such as evaporation or extraction, and may be purified by standard methods such as distillation, recrystallization or chromatography.

EXAMPLES

The compounds of the following examples are represented in the above Schemes 1-6 and named using Spetagam software OPyga. In addition to the abbreviations described above, taking into account the Schemes provided in this context, the following abbreviations are used in the examples. "HPLC" - high-performance liquid chromatography, "IR" - in process; "MI" - mother solution; "BRIDGE" - no less than; "MShMT" - no more than; "AB" - round-bottomed (bulb); "VT" - room temperature; "zt" - starting substance; "OSM" - dichloromethane.

Unless otherwise specified, the compounds are characterized by HPLC and H-NMR analysis and used in subsequent reactions, with or without purification. H-NMR analysis is performed at 400 MHz, unless otherwise specified. Unless otherwise specified, product yield/purity is determined by mass, by qNMR analysis and/or by HPLC analysis.

Example 1. Synthesis of tert-butyl-4-bromo-2-fluorobenzoate (Compound (0)

4-bromo-2-fluoro-1-iodobenzene, Compound (A) (5 g, 1.0 eq.-) and THF (25 ml) are introduced into a 100 mL jacketed reactor equipped with a mechanical stirrer. The solution is cooled to a temperature of -5 "C. A 2M solution of magnesium isopropyl chloride in THF (10.8 ml, 1.3

From eq.), maintaining the internal temperature below 0 "C. The mixture is stirred at a temperature of 0 "C for 1 hour. Add di-tert-butyl dicarbonate (5.44 g, 1.5 equiv.) in THF (10 mL). After 1 hour, the solution is quenched with a 10 95 solution of citric acid (10 ml) and then diluted with a 25 95 solution of Masi (10 ml). The layers are separated and the organic layer is concentrated almost to dryness and treated with THF (3 times 10 ml each). The crude oil is diluted with THF (5 ml), filtered to remove inorganic substances and concentrated to dryness. Crude oil (6.1 g, efficiency - 67 95, yield determined by efficiency - 88 95) is used at the next stage without further purification. "H-NMR (DMSO-α): 6 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, 9U-10.5, 1.9 Hz, 1H), 7.74 (t, 928.2 Gu, 1H).

Example 2. Synthesis of tert-butyl-2-(1H-pyrrolo(2,3-b|Ipyridin-5-yl)/oxy)-4-bromobenzoate (Compound (0))

1H-pyrrolo|2,3-b|Ipyridin-5-ol (80.0 g, 1.00 equiv.), tert-butyl-4-bromo-2-fluorobenzoate (193 g , 1.15 eq.) and anhydrous DMF (800 mL). The mixture is stirred at a temperature of 20 "C for 15 minutes. The resulting solution is cooled to a temperature from approximately zero to 5 "C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 ml) is added slowly over 30 minutes, all the while maintaining the internal temperature no higher than 10 "C, and washed with DMF (30 ml). The reaction mixture is stirred at a temperature of 10 C for 1 hour (not quite white suspension) and set the internal temperature equal to "45 "C for 30 minutes. The reaction mixture is stirred at a temperature of 45-50 C for 7 hours and the course of the reaction is monitored using

HPLC (IR samples: 92 90 conversions, at 9o by HPLC). The solution is cooled to a temperature of "20 76.

This solution is stirred at a temperature of 20 "С during the night.

Water (1200 ml) is slowly added to the reaction mixture at a temperature of "30"C for 1 hour (slight exothermic reaction). The resulting suspension is brought to a temperature of approximately 20"C and stirred for at least 2 hours. The crude product is collected by filtration and washed with water (400 ml). The wet filter cake was washed with heptane (400 mL) and dried under vacuum at 50 °C overnight to give the crude product (236.7 g).

Recrystallization or re-suspension: 230.7 g of the crude product (as determined by efficiency: 200.7 g) is introduced into a three-necked Morton flask with a capacity of 3 l. Ethyl acetate (700 mL) was added and the suspension was slowly heated to reflux for 1 hour (a small amount of solids remained). Heptane (1400 ml) was added slowly and the mixture was refluxed (78 C). The suspension is stirred at reflux for 30 minutes and slowly cooled to about -10 °C at a rate of about °C/hour and stirred for 2 hours. The product is collected by filtration and washed with heptane (200 mL).

The solid was dried in vacuo at a temperature of about 50 °C overnight to give 194.8 g; the yield of isolated product as an off-white solid was 86 95.

M5-E5I: 389.0 (M--1); melting point: 190-191 "C (not corrected). "H-NMR (DMSO-ab): 6 1.40 (s, 9H), 6.41 (dd, U-3.4, 1.7 Hz, 1H), 7.06 (d, 9-1.8 Hz, 1H), 7.40 (dd, 98.3, 1.8 Gu, 1), 7.51 (t, 9U-34 Hz, 1H) , 7.58 (d, U-2.6 Hz, 1H), 7.66 (d, 9U-8.3 Hz, 1H), 8.03 (d, u2.7 Hz, 1H), 11.72 (c, 1H, MN).

Example 3. Synthesis of 2-chloro-4,4-dimethylcyclohexanecarbaldehyde (Compound (E))

Anhydrous DMF (33.4 g, 0.456 mol) and CNOsig (80 ml) are introduced into a round-bottom flask with a capacity of 500 ml. The solution is cooled to a temperature of "-5"C and slowly added РОСсСииз (64.7 g, 0.422 mol) for 20 minutes at a temperature of "20 "С (exothermic reaction), washed with SNeSi" (b ml). The slightly brown solution is brought to a temperature of 2070 for 30 minutes and stirred at a temperature of 20 C for 1 hour. The solution is cooled to a temperature of "5" C. Add 3,3-dimethylcyclohexanone (41.0 g, purity 90 95, -0.292 mol) and wash with CNeSig (10 ml) (slight exothermic reaction) at a temperature of "20 "C. The solution is refluxed and stirred overnight (9 p.m.).

130 g of 13.6 95 wt. aqueous solution of sodium acetate trihydrate, 130 g of 12 U-th saturated salt solution and 130 ml of СНеСи». The mixture is stirred and cooled to a temperature of "5 76.

The above-mentioned reaction mixture (transparent and brown in color) is transferred, it is slowly quenched, all the time maintaining the internal temperature of "10" C. The reaction vessel is rinsed after

With the help of SNeoSi»g (10 ml). The quenched reaction mixture is stirred at a temperature of "1070 for 15 minutes and the temperature is raised to 20 "C. The mixture is stirred at a temperature of 20 "C for 15 minutes and left to settle for 30 minutes (to some extent the emulsion). The lower organic phase is separated. The upper aqueous phase is extracted again with the help of SNesi" (50 ml). The combined organic layers are washed with a mixture of: 12 95% saturated saline solution (150 g) - 20 9% aqueous KzROx solution (40 g). The organic layer is washed over

Maz5o", filtered and washed with SneoSi" (30 ml). The filtrate is concentrated to dryness in a vacuum, obtaining a brown oil (57.0 g, efficiency - 90.9 95 wt.

NMR, 100 Ob). "H-NMR (SOSyz): b 0.98 (s, 6H), 1.43 (t, 9-6.4 Hz, 2H), 2.31 (tt, 9-64, 2.2 Hz, 2H ), 2.36 (t, 9-22

Hu, 2H), 10.19 (s, 1H).

Example 4. Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde (Compound (C))

2-chloro-4,4-dimethylcyclohex-1-encarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g) and acetonitrile (10 ml) are introduced into a thick-walled flask with a capacity of 250 ml. The mixture is stirred at a temperature of 20 "С for 5 minutes. Add 21.0 95 wt. of an aqueous solution

KSO" (76.0 g). The mixture is stirred at room temperature for at least 5 minutes, then 4-chlorophenylboronic acid (9.53 g) is added all at once. The mixture is vacuumed three times and purged with nitrogen. Palladium acetate (66 mg, 0.5 Fo mol.) is added all at once under a nitrogen atmosphere. The reaction mixture is evacuated three times and purged with nitrogen (the mixture is colored orange). The flask is filled with nitrogen and heated to a temperature of -35 C in an oil bath (the temperature of the bath is "35 "C). The mixture is stirred at a temperature of 30 C overnight (15 hours). The reaction mixture is cooled to room temperature and the IR sample is extracted from the upper organic phase to determine the completion of the reaction, usually the starting substance is "2 95 (the mixture is colored in orange color). Toluene (100 ml) and an aqueous solution of 5 95 ManHSO - 2 95 I -cysteine (100 ml) are added. The mixture is stirred at a temperature of 207 for 60 minutes. The mixture is filtered through a layer of Celite to remove the black solid, the flask and the Celite layer are washed with toluene (10 ml). The upper organic phase is repeatedly washed with an aqueous solution of 595 MaNsSoO»z - 2 95 I - cysteine (100 ml). The upper organic phase washed with 25% saturated saline (100 ml). The organic layer (105.0 g) was analyzed (118.8 mg/g, 12.47 g of products by analysis, the yield by analysis was 87.90) and concentrated to " 1/3 of the volume (735 ml). The solution of the product is directly used in the next stage, without separating the product. However, the sample for analysis is obtained by removing the solvent, yielding a brown oil. "H-NMR (SOCI3): 6 1.00 (s, 6H), 1.49 (t, 9-6.6 Hz, 2H), 2.28 (t, 9-21 Hz, 2H), 2, 38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).

Example 5. Synthesis of tert-butyl-4-((4-chloro-5,5-dimethyl-3,4,5,6b-tetrahydro-(1,1"-biphenyl|-2-yl)umethyl)piperazin-1 -carboxylate (Compound (H))

A solution of 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-(1,1"-biphenyl|-2-carbaldehyde (50, 0 g) in toluene (250 ml), BOC-piperazine (48.2 g) and anhydrous THF (250 ml). The yellow solution is stirred at a temperature of 20 "С for 5 minutes. Sodium triacetoxyborohydride (52, 7 g) (note: the internal temperature rises to 29.5 °C within 15 minutes, cooling may be necessary). The yellow mixture is stirred at a temperature of x25 °C for at least 4 hours. The conversion of the starting substance to the product, which is 99, 5 95, monitored by HPLC, after 3 hours of reaction time.

To quench the reaction, slowly add 12.5 90 wt. saturated salt solution (500 g).

The mixture is stirred at a temperature of 20 "C for at least 30 minutes and left to settle for at least 15 minutes. The lower aqueous phase (7560 ml) is separated (note: some emulsion remains in the upper organic phase). The organic phase is washed with 10 95 citric acid solution (2 times 500 g each). 500 g of a 95% aqueous solution of MansSoz is slowly introduced into the flask. The mixture is stirred at a temperature of 20 "C for at least 30 minutes, and left to settle for at least 15 minutes . The upper organic phase is separated. Enter 500 g of 25 U6 aqueous saturated salt solution.

The mixture is stirred at a temperature of 20 "C for at least 15 minutes, and left to settle for at least 15 minutes. The upper organic phase is concentrated to a volume of -200 ml in a vacuum. The solution is brought to a temperature of -30 "C and the inorganic salt is filtered off . Toluene (50 ml) is used as a washing agent. The combined filtrate is concentrated to a volume of "100 ml. Add acetonitrile (400 ml) and heat the mixture to a temperature of -80C to obtain a clear solution. The solution is slowly cooled to a temperature of 20 °C at a rate of 10 °C/hour and stirred at

From a temperature of 20 "C during the night (the product crystallizes at a temperature of "45-50 C, if necessary, the seed material can be added at a temperature of 502 C). The suspension continues to be slowly cooled to a temperature of "10 C at a rate of 10 "C/h. The suspension is stirred at a temperature of -107C for at least 6 hours.

The product is collected by filtration and washed with pre-cooled acetonitrile (100 ml). The solid substance is dried in a vacuum at a temperature of 50 "С during the night (72.0 g, yield 85 Ob).

M5-E5I: 419 (M.-1); melting point: 109-110 "C (not corrected). "H-NMR (SOCI3): 6 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, 9-6, 5 Hz, 2H), 2.07 (s, width, 2H), 2.18 (m,

AN), 2.24 (t, U-6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 ( m, 2H).

Example 6. Synthesis of 1-(4-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-(1,1'-biphenyl/|-2-yl)umethyl)piperazine dihydrochloride (Compound (1))

In a three-necked round-bottom flask with a capacity of 2.0 L, equipped with a mechanical stirrer, introduce

BOSsS-product of reductive amination (Compound (H), 72.0 g) and IRA (720 ml). The mixture is stirred at room temperature for 5 minutes and 59.3 g of a concentrated aqueous solution of hydrogen chloride is added to the suspension. The internal temperature of the reaction mixture is brought to 6570 (a clear and colorless solution is obtained). The reaction mixture is stirred at a temperature of -65 "C for at least 12 hours.

The suspension of the product is slowly cooled to a temperature of -5°C (10°C/hour). The product suspension is stirred at approximately -5 °C for at least 2 hours, the product is collected by filtration. The wet filter cake is washed with IRA (72 mL) and dried at 50 °C under vacuum overnight to yield 73.8 g (yield 95,905) of the desired product in the form of a solvate of IRA bishydrochloride (purity »99.5 95, peak area at 210

NM).

M5-E5I:319(M-1). "H-NMR (020): δ 1.00 (s, 6H), 1.19 (d, U-6.0 Hz, 6H, IRA), 1.65 (t, 9U-6.1 Hz, 2H ), 2.14 (s, width, 2H), 2.26 (m, 2H), 3.36 (width, 4H), 3.55 (s, width, 4H), 3.82 (s , 2H), 4.02 (septet, U-6.0 Hu, 1H,

IRA), 7.16 (d, U-8.1 Hz, 2H), 7.45 (d, 9-81 Hz, 2H). "H-NMR (SOSiz): b 0.86 (s, 6H), 1.05 (d, U-6.0 Hz, 6H, IRA), 1.42 (t, 9-6.1 Hz, 2H ), 2.02 (s, width, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, width, 4H), 3.68 (s, 2H), 3.89 (septet, U-6.0 Hz, 1H, 60 IRA), 7.11 (d, U-8.1 Hz, 2H), 7.41 (d, 9-81 Hz, 2H ).

Example 7. Synthesis of 3-nitro-4-"((tetrahydro-2H-pyran-4-yl)umethyl)amino)-benzenesulfonamide (Compound (M))

4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-ylumethanamine (7 .0 g) and acetonitrile (150 ml). The internal temperature of the reaction mixture is set to 80 "C and stirred for at least 12 hours.

The product solution is cooled to a temperature of 40 "C and stirred for at least 1 hour until precipitation is observed. The product suspension is further cooled to a temperature of 20 "C. Water (75 mL) is introduced slowly over a period of at least 1 h, and the mixture is cooled to 10 °C and stirred for at least 2 h before collecting the product by filtration. The wet filter cake is washed with a mixture of acetonitrile:water (40 ml, 1:1).The wet filter cake is then resuspended in water (80 ml) at a temperature of 40 °C for at least 1 hour before collecting the product by filtration. The wet filter cake is washed with water (20 ml) and dried at a temperature of 75 °C in a vacuum, obtaining 12.7 g of the desired product with a purity of 99.995 and an established mass yield of 91 9. "H-NMR (DMSO-dv): 6 1, 25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H ), 7.27 (d, 9-9.3 Hz, 1H), 7.32 (s, МН», 2H), 7.81 (dd, 9-91, 2.3 Hz, 1H), 8, 45 (d, 9-2.2 Hz, 1H), 8.54 (t, 9-5.9 Hz, 1H, МН).

Example 8. Synthesis of tert-butyl-2-(1H-pyrrolo(|2,3-b|Ipyridin-5-yl)uoxy)-4-(4-((4-chloro-5,5-dimethyl-3, 4,5,6-tetrahydro-(1,1'-biphenyl1-2-yl)umethyl)piperazin-1-yl)benzoate (Compound (K))

General Considerations: In the case of this chemical process, air and moisture sensitivity are taken into account.

While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent can render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidizing agents (eg, peroxides contained in the solvent) must be removed before combining the catalyst precursors with the solvent, and care must be taken when using them to prevent access of oxygen during the reaction. Also, you have to worry about

From the use of dry equipment, solvents and reagents to prevent the formation of unwanted by-products. The sodium tert-butoxide used in this reaction is hygroscopic and must be properly handled and stored before or during use.

Bishydrochloride (Compound (I), 42.5 g) and toluene (285 ml) are introduced into a 2.0 L three-neck round-bottom flask equipped with a mechanical stirrer. Add 20 95% KzRoOx solution (285 ml) and the two-phase mixture is stirred for 30 minutes. The layers are separated and the organic layer is washed with a 25-95 solution of MacCl (145 ml). The organic layer is concentrated to 120 g and used in the binding reaction without further purification.

MaoiVy (45.2 g) and Compound (I) in the form of a solution in toluene (120 g solution - 30 g established efficiency) are combined with THF (180 ml) in a suitable reactor and bubbled with nitrogen for a time of at least 45 minutes. Ragabraz (0.646 g), Compound (U) (0.399 g) and Compound (0) (40.3 g) are combined in a second suitable reactor and purged with nitrogen until the oxygen level reaches at least 40 ppm. Using nitrogen pressure, a solution containing Compound (I) and MasbiVy in a toluene/THF mixture is added through a 0.45 μm filter to the second reactor (catalyst, Compound (U) and Compound (0)) and rinsed with a bubbler nitrogen THF (30 ml).

The resulting mixture is heated at a temperature of 55 "C, with stirring, for at least 16 hours, then cooled to a temperature of 22 "C. The mixture is diluted with 12 95% Masi solution (300 g), then with THF (300 ml). The layers are separated.

The organic layer is mixed with a freshly prepared solution of I-cysteine (15 g), MansSOOz (23 g) and water (262 ml). After 1 hour, the layers are separated.

The organic layer is mixed with the second freshly prepared solution of I-cysteine (15 g),

Manso: with (23 g) and water (262 ml). After 1 hour, the layers are separated. The organic layer is washed with 12 U6 solution of Masi (300 g), then filtered through a filter with a thickness of 0.45 μm. The filtered solution is concentrated under vacuum to a volume of 300 ml and washed three times with heptane (600 ml each time) to remove TI F.

The crude mixture is concentrated to b volumes and diluted with cyclohexane (720 ml). The mixture is heated to a temperature of 75 °C, kept for 15 minutes and then cooled to a temperature of 65 °C for a period of at least 15 minutes. Inoculum is introduced and the mixture is kept at a temperature of 65 "C for 4 hours. The suspension is cooled to a temperature of 25 "C for at least 8 hours, then heated at a temperature of 25 70 for 4 hours. The solids are filtered and washed with cyclohexane (90 ml) and dried at a temperature of 50 "C in a vacuum.

52.5 g (yield 88.9 95) of a white solid is isolated. Melting point (not corrected): 154-155 70. "H-NMR (DMSO-α): b 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, U-6 .4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, bH), 2.74 (s, 2H), 3.02-3.19 (m, 4H) , 6.33 (dd, 9-34, 1.9 Hz, 1H), 6.38 (d, 9-24 Hz, 1H), 6.72 (dd, 929.0, 2.4 Hz, 1H) , 6.99-7.06 (m, 2H), 7.29 (d, U-2.7 Hz, 1H), 7.30-7.36 (m, 2H), 7.41-7.44 (m, 1H), 7.64 (t, 9-6.7 Gu, 1H), 7.94 (d, 9-2.7 Hz, 1H), 11.53 (s, 1H).

Example 9. Synthesis of 2-(1H-pyrrolo(|2,3-b|Ipyridin-5-yl)oxy)-4-(4-(4-chloro-5,5-dimethyl-3,4,5,6 - tetrahydro-(1,1"-biphenyl|-2-yl)umethyl)piperazin-1-yl)benzoic acid (Compound (I))

Preparation of the solution: 10 U6 aqueous solution of KNeroX:: KNeRO»X (6 g) in water (56 g); 2:71, heptane/2-MetHF-heptane (16 mL) in 2-MetTHF (8 mL).

Compound (K) (5.79 g), potassium t-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL) and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated at 55 "C until the reaction is complete. The reaction mixture is cooled to a temperature of 22 "C, washed twice with a 10 9% solution of KNeRoh (31 g). The organic layer is then washed with water (30 g).

After removing the aqueous layer, the organic layer is concentrated to 4 volumes (419 ml) and heated at a temperature not less than 50 "C. Heptane (23 ml) is slowly added.

Alternatively, after removing the aqueous layer, the organic layer is concentrated to 5 volumes and heated to a temperature of at least 70 °C, and 5 volumes of heptane are slowly added. The resulting suspension is cooled to a temperature of 10 °C. The solids are then collected by vacuum filtration, with liquid recirculation, and the filter cake is washed with a mixture of heptane/2-MetHF (24 mL, 2:1). The solids are dried at a temperature of 80 "С in a vacuum, obtaining 4.0 g of Compound (I) with a mass yield of approximately 85 95. "H-NMR (DMSO-α): b 0.91 (s, 6Н), 1 .37 (t, U-6A Hz, 2H), 1.94 (s, width, 2H), 2.15 (m, 6H), 2.71 (s, width, 2H), 3.09 ( m, 4H), 6.31 (d, 9U-22.3 Hz, 1H), 6.34 (dd, U-3.4, 1.9 Hz, 1H), 6.7 (dd, U-9 ,0, 2,4

Gu, 1), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, 9-26 Hz, 1H), 7.44 (t, 9U-3.0 Hz, 1H), 7.72 (d, 9U-9.0 Hz, 1H), 7.96 (d, 9-2) Hz, 1H) and 11.59 (m, 1H).

From Example 10. Synthesis of 4-(4-C2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl|methyl)piperazin-1-yl)-M-(3-nitro-4- Ctetrahydro-2H-pyran-4-ylmethyl)amino|-phenyl)usulfonyl)-2(1H-pyrrolo|2,3-

BIpyridin-5-yloxy)benzamide (Compound (1))

Preparation of the solution before introduction into the interaction: 10 9% solution of acetic acid: acetic acid (37 ml) in water (333 g); 5 95th MansSoz solution: Mansoz (9 g) in water (176 g); 5 95th Mass solution: Mass (9 g) in water (176 g).

Compound (M) (13.5 g), OMAR (10.5 g), ERAS (10.7 g) and dichloromethane (300 ml) are combined in a suitable reactor and stirred at a temperature of 25 "C. Acid is introduced into the second suitable reactor (Compound (I), 25 g), EizM (8.7 g) and dichloromethane (120 ml). The resulting acid solution (Compound (I)) is slowly introduced into the initial suspension of Compound (M) and stirred until the reaction is complete Then, in the reaction mixture, with continuous stirring, it is introduced

M,M-dimethylethylenediamine (9.4 g). The reaction mixture is heated to a temperature of 35 "С and washed twice with a 10 95 solution of acetic acid (185 ml). The lower organic layer is further diluted with dichloromethane (75 ml) and methanol (12.5 ml). The organic layer containing the product, then washed with a 5 9% solution of MaHsSoO:z (185 ml) and then washed with a 5 95% solution

Mass (185 ml), at a temperature of 35 "C. The lower organic layer is separated and then concentrated to 8 volumes (7256 ml), diluted with methanol (26 ml) and heated to a temperature of 38 C.

Ethyl acetate (230 ml) is introduced slowly. The resulting suspension is slowly cooled to a temperature of 10 "С and then filtered. The wet filter residue is washed twice with a mixture of dichloromethane and ethyl acetate (1:11, 72 vol., 64 ml). After drying the filter residue at a temperature of 90 "С, 32 g are isolated (yield 84 95) Compounds (1). "H-NMR (DMSO-α): b 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, 9U-6.4 Hz, 2H), 1.60 (m , 2H), 1.87 (m, 1H), 1.93 (s, width, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, width ., 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, 9-21 Hz, 1H), 6.37 ( dd, 9-34, 1.9 Hz, 1H), 6.66 (dd, 9-91, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, ZN), 7.78 (dd, 3-9.3, 2.3 Hz, 1H), 8.02 (d, 9-2, 61 Hz, 1H), 8.54 (d , у2, 33 Hz, 1Н), 8.58 (t, У-5.9 Hz, 1Н, МН), 11.65 (m, 1Н).

Example 11. Synthesis of (18,4НА)-4-hydroxy-4-methylcyclohexyl)methanaminium-4-methylbenzenesulfonate

Stage A. 1.49 g of cyclohexanedione monoethylene acetal (1.0 equiv.) and 15 ml of toluene are introduced into a suitable reactor. The mixture is stirred for 30 minutes at a temperature of 10 "C. A 1.4 M solution of methylmagnesium bromide (2.32 equiv.) in a mixture of toluene-THF (75-25) is introduced into another reactor and stirred at a temperature of 15 "C. The solution of the starting substance is added dropwise to the solution of the Grignard reagent, at a temperature of approximately 10-20 "С, for 4 hours (the rate of addition is 0.1 ml/min). The course of the reaction is observed using TLC. After the completion of the reaction, the reaction mixture is slowly introduced into a 24% ammonium chloride solution (20 ml) at a temperature of 25 °C. The reaction mixture is stirred and settled, the organic layer is separated, and the aqueous layer is extracted with ethyl acetate (3 times 20 ml each). The combined organic layers are filtered through a layer of sodium sulfate and the filtrate is concentrated by distillation to dryness. 1.57 g of crude solids are isolated (yield 95 95) and transferred to the next stage. "H-NMR (400 MHz, chloroform-a:): b 3.88-4.01 (m, 4H), 1.85-1.96 (m, 2H), 1.08-1.64 (m , 7H).

And CM5-(M5 310 and 292). VI-0.074 by TLC (hexane-EIOAc-1-1).

Stage B. 18 ml of 0.005 N hydrochloric acid (0.02 equiv.) is added to the residue after distillation from stage A. The reaction mixture is stirred at 70 °C for 3 hours and monitored by TLC. After completion of the reaction, the reaction mixture is cooled to a temperature of 25 "C and introduced into another suitable reactor containing 22 ml of 5 95% sodium chloride solution. The reaction mixture is stirred until all the salt is dissolved, then extracted with ethyl acetate (8 times 200 ml each). The combined organic layers are filtered through a layer of sodium sulfate and the filtrate is concentrated by distillation to dryness. The product is isolated (yield 99.38 95) and directly used in the next stage. "H-NMR (400 MHz, chloroform-a:): b 2.68-2.80 (m, 2H), 2.16-2.39 (m, ЗН), 1.77-2.04 (m , 4H), 1.41 (c, ЗН), 1.33 (c, 1H).

Stage C The product from stage B (0.25 g) is dissolved in toluene (5 ml) in a three-necked flask with a capacity of ml, equipped with a Dean-Stark trap. Nitrogen is bubbled through the reactor to remove air.

0.585 g of nitromethane (5 equiv.), then 0.052 g of M,.M-dimethylethylenediamine (0.3 equiv.) are introduced into the reactor. The reaction mixture is refluxed, water is removed using a 25 Dean-Stark trap. The reaction mixture is stirred at reflux for 1 hour and monitored by HPLC analysis. The reaction mixture is then cooled to a temperature of 20 "C, when the product is stabilized according to HPLC analysis, then treated with EtOAc and heptane and concentrated to dryness. The residue is purified on a SotbriNiazi column (column, weight 12 g) using a mixture of hexane/E(OAc - from 80-20 to 60-

From 40. The fractions are analyzed by HPLC and TLC, the fractions containing the product are distilled to dryness. 0.23 g of concentrated oil is obtained (yield 68.09 95) and used at stage 0. "H-NMR (400 MHz, chloroform-α): b 5.88-5.90 (width s, 1H), 4.88-4.89 (width s, 2H), 2.16-2.40 (m, 4H), 1.78-1.85 (m, 1H), 1.33 (s, ЗН).

Stage 0. Crabtree's catalyst (0.471 g, 0.585 mmol) is introduced, under nitrogen, into a 450 mL stirred standard specification Parr reactor. The reactor is purged with nitrogen and a solution of (5)-1-methyl-4-(nitromethyl)cyclohex-33-enol (34.88 g, 58.5 mmol) is introduced into

OSM (100 ml). An additional amount of nitrogen sparged UOSM (80 ml) is added, the reactor is purged with argon, hydrogen and a hydrogen pressure of 100 psi is created. inch. The mixture is stirred for 4 hours at a temperature of 30 "C. The course of the reaction is observed with the aid of

NMR, concentrate to an oil, treat twice with THF (50 mL), then dilute with THF (50 mL). The product is then transferred, for further reduction using Raney nickel, to stage E. "H-NMR (chloroform-a:): b 4.33 (d, 9-7.3 Hz, 2H), 4.32 (9- 6.5 Hz, 1H), 2.36-2.20 (m, 1H), 1.92-1.69 (m, 1H), 1.64-1.40 (m, 1H), 1.39 -1.18 (m, 1H).

Stage E. Nickel Raney (ala-1) or "7/6) - 2.04 g (20 95 wt.) Washed several times with subsequent decantation using THF. Nickel Raney, a solution of (1H,48)-1- of methyl-4-(nitromethyl)cyclohexanol and THF (50 mL), under nitrogen, was introduced into a 450 mL stirred standard specification Parr reactor, which was purged with nitrogen, hydrogen, and hydrogenated at 40 psig. inch, for 4 hours, at a temperature of 50 "C. The reaction is monitored with C and, after completion, the reaction mixture is filtered through a polypropylene filter funnel with diatomaceous earth/polyethylene fritted disc to remove the catalyst. THF is used as a rinsing agent for the extraction of the residual product from the filter sediment.

The combined filtrate is an amber solution, which is directly transferred to the next stage. "H-NMR (400 MHz, chloroform-a): b 2.61 (d, 9U-6.5 Hz, 2H), 1.25-1.50 (m, 12H), 0.80-1.17 (m, zn).

Stage R. 9.86 g of the solution from stage E is added to a 500 ml round-bottom flask and distilled to dryness, treated twice with acetonitrile and then dissolved in acetonitrile (100 ml). Hydrate of 4-methylbisol sulfonic acid (11.68 g) is added to the solution, after which the solid substance is precipitated and the temperature is raised to 40 "C. The suspension is stirred at a temperature of 50 "C for 2 hours and cooled to a temperature of 20 "C for 12 hours.

The solids are filtered off and washed with 40 ml of acetonitrile. The wet filter cake was dried in vacuo to give 14.24 g of product (yield 77 95). "H-NMR (400 MHz, deuterium oxide-a?2): 6 2.79 (d, 9-7.0 Hz, 2H), 1.48-1.68 (m, 5H), 1.31- 1.46 (m, 2H), 0.90-1.29 (m, 5H).

Example 12. Synthesis of 4-4 1A,4H)-4-hydroxy-4-methylcyclohexyl|methyl)-amino)3-nitrobenzenesulfonamide (Compound (P)) 4-Chloro-3-nitrobenzenesulfonamide (6.5 g, 27.5 mmol) and (((18,48)-4-hydroxy-4-methylcyclohexyl)methanaminium-4-methylbenzenesulfonate (11.26 g, 35.7 mmol) are combined in 35 ml of acetonitrile and stirred. M,M -diisopropylethylamine (8.88 g, 68.7 mmol), at ambient temperature, resulting in endothermy (from 200"С to 17.57С). After 10 minutes, the reaction mixture is heated to a temperature of 807 and settled at the same temperature for 24 hours. The reaction was monitored for completion by HPLC. After the reaction was complete, the reaction mixture was cooled to 40° C. After 15 minutes, water (32.5 mL) was added and allowed to stand for 30 minutes.

An additional 74.5 ml of water is added over 30 minutes. A solid product precipitates shortly after the addition of a second portion of water. After stirring for 1 hour at 40°C, the mixture containing the product is allowed to cool to 20°C, stirred for 12 hours, and then cooled to 0°C with stirring for an additional 2 hours. The product is filtered and dried in a vacuum, obtaining 8.8 g of product (yield 93 90; purity 299 9, ch.d.a.). "H-NMR (400 MHz, DMSO-α): b 8.52 (t, 9-5 .9 Hz, 1H), 8.45 (d, U-2.2 Hz, 1H), 7.80 (dd, 9-91, 2.3 Hz, TN), 7.24-7.30 (m , ЗН), 4.23 (s, 1Н), 1.60-1.74 (m, ЗН), 1.52-1.57 (m, 2Н), 1.26-1.40 (m, 2Н ), 1.06-1.25 (m, 5Н).

Example 13. Synthesis of 4-(4-C2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl|methyl)piperazin-1-yl)-M-(3-nitro-4-K1H ,4НА)-(4-hydroxy-4-methylcyclohexyl|-methyl)amino|phenylsulfonyl)-2- (IN-pyrrolo(2,3-B|Ipyridin-5-yloxy)benzamide (Compound (2))

Sulfonamide, 4-(C((18,4H)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-

Co) nitrobenzenesulfonamide (8.00 g, 23.29 mmol), EUBAS-NSI (5.80 g, 30.3 mmol) and OMAR (8.54 g, 69.9 mmol) are stirred in OSM (186 ml, 14 vol.) until the formation of a golden colored suspension.

Add a solution of acid, 2-(1H-pyrrolo(2,3-b|Ipyridin-5-yl)oxy)-4-(4-((4-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-(1,1"-biphenyl|-2-yl)umethyl)piperazin-1-yl)benzoic acid (13.3 g, 23.29 mmol) and TEA (6.49 mL, 46.6 mmol) ) in OSM (80 mL, 6 vol.) for 2.5 h using a dropper, then rinsed with 10 mL OSM. After stirring for 12 h, add M1,M1-dimethylethane-1,2-diamine ( 5.09 ml, 46, mmol) and continue to stir at a temperature of 20 "С for 5 hours. The reaction mixture is washed with 10 95% HOAc solution (3 times 130 ml each). The organic layer is washed with 5 95% ManHCO3 solution (140 ml ) and 5% Massey solution (140 ml). The organic layer is dried over Mag5O" and concentrated to 7 volumes of OSM solution. Methanol (10 vol., 140 ml) is added dropwise over 2 hours, and the solution cooled to a temperature of 15 °C, after which the product precipitates. The mixture containing the product is cooled to a temperature of 5 °C and stirred for 2 hours. After filtering the product milk substance and drying with the help of nitrogen blowing for 2 hours, 17.35 g of product are obtained (yield 83,905; purity (99.5,905, ch.d.a.). "H-NMR (400 MHz, DMSO-av): b 11.57-11.59 (width, 1H), 8.48-8.52 (m, 2H), 7.97 (d, U-2 ,6 Gu, 1H), 7.73 (dd, 9U-9.2, 2.3 Gu, 1H), 7.43-7.50 (m, ZN), 7.29-7.31 (m, 2H), 6.98-7.03 (m, ЗН), 6.65 (dd, 98.9, 2.3 Hz, 1H), 6.35 (dduU-3.4, 1.8 Gu, 1H ), 6.16 (d, 9U-2.2 Gu, 1H), 4.41-4.44 (m, 1H), 3.71-3.75 (m, 2H), 2.98-3, 51 (m, 11H), 2.74-2.76 (m, ЗН), 2.02-2.26 (m, 6H), 1.88-1.92 (m, 2H), 1.47- 1.70 (m, 5H), 1.24-1.40 (m, 4H), 1.08 (s, 5H), 0.89 (s, 6H).

All references cited herein are hereby incorporated by reference in their entirety.

While the methods contemplated herein are described with particular embodiments in mind, it should be apparent to one skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention as set forth in the appended claims.

It is intended that the embodiments described above are exemplary only, and that one skilled in the art should recognize, or should be able to establish, using no more than ordinary experimentation, numerous equivalents of specific compounds, substances, and methods. All such equivalents are within the scope of this invention and are covered by the appended claims. (510)

Claims (24)

FORMULA OF THE INVENTION 1. The method of obtaining the compound of the formula A1: nm M X - MO, cho, w in MN M M Ge) in" TU XM o s (Al) on d) "where ., where B? choose from: and and ; which includes : (a) combining a compound of the formula (K): sov (c) FI; -- М М Н З М сх ; (Кк) where В means C1-C12-alkyl, with tert-butoxide, an aprotic organic solvent and water, to obtaining the compound of formula (I): sleep (c) If; - m y s M сх щВ and (6) combining the compound of the formula (3) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, an organic solvent and or with the compound of the formula (M), to obtain the compound of the formula (At ), where B? Kk" means: ; МО, Н M (o); M 0-35 МН, 9 (m) or with the compound of formula (P), to obtain the compound of formula (AT), where B? means: KO mo, (c) nm Y MH i he Y also c) -, ; (P) thus obtaining the compound of formula (AL), where the compound of formula (K) is obtained as follows: (4) combining the compound of formula (0) sor (c) ги- МН Вг (0) with the compound of formula (I) Н M (С Z гне М сх и a source of palladium, tert-butoxide and phosphine ligand in an aprotic organic solvent, obtaining the compound of formula (K). Kk» 2. The method according to claim 1, where B: means: ; The first stage (B") includes: (6) combining the compound of the formula (3 with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, an organic solvent and the compound of the formula (M): MO, H M (6) M 0-35 MN, o (m) to obtain the compound of formula (A1). 3. The method according to claim 1, where B2 is , WHICH additionally includes: (c") combining the compound of the formula (M) МО, СИ (6) М 0-5 МН 7 (М) with a base in the form of a tertiary amine, an organic solvent and (tetrahydro-2H-pyran-4-ylomethanamine or its salt, to obtain the compound of formula (M). 4. The method according to claim 1, where B2 is and , WHICH additionally includes: (c") combining the compound of the formula (M) ko) MO, SI (6) M 0-3 Mn, (m) with a base in the form of a tertiary amine, an organic solvent and (1A,4H8)-4-(aminomethyl)-1-methylcyclohexanol or its salt, to obtain a compound of the formula (P ). 5. The method according to any one of claims 1-4, where, at stage (a), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. 6. The method according to any one of claims 3-5, where, at stage (c"), the base in the form of a tertiary amine is M,M-diisopropylethylamine. 7. The method according to any one of claims 1-6, where the compound of formula (I) is combined with the base before combining in stage (4). 8. The method according to any one of claims 1-6, wherein, in step (4), the source of palladium is Ragabaz or Kcinnamite Rasi|». 9. The method according to any of claims 1-8, where the phosphine ligand in stage (4) is a compound of the formula (U): p M Me ? (7). 10. The method according to any one of claims 1-9, where the source of palladium is Ragaraz, the catalytic amount of Ragaraz is used in accordance with the amount of compound (I), and where the catalytic amount of Ragaraz is from about 0.5 to 95 mol. to about 2 95 mol. 11. The method according to claim 9 or 10, where the catalytic amount of the compound of the formula (U) is used in accordance with the amount of the compound (I), and where the catalytic amount of the compound of the formula ()) is from approximately 1 95 mol. to about 5 95 mol. 12. The method according to any one of claims 1-11, where, in stage (4), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. 13. The method according to any one of claims 1-12, where the method further includes: (i) combining the compound of the formula (B) with the compound of the formula (C) so E no g m M Pov B (c) and with tert-butoxide , in an organic solvent, to obtain the compound of formula (0). 14. The method according to claim 13, where, at stage (is), tert-butoxide is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. 15. The method according to any one of claims 13 or 14, which additionally includes: Zo (Y) combining the compound of formula (A) with V'MaH, in an aprotic organic solvent; where V! means C1-C6-alkyl and X means CI, Bg or I; (9) combining C1-C12-alkyl chloroformate or di(C1-C12-alkyl)udicarbonate with the product from stage (I) to obtain the compound of formula (C). 16. The method according to claim 15, where, in stage (1), B' means isopropyl. 17. The method according to claim 15 or 16, where, at stage (Her), B means tert-butyl, and di(C1-Ci2-alkyl dicarbonate is di-tert-butyl dicarbonate. 18. The method according to any one of claims 1-17, which additionally includes: (n) combining the compound of formula (E) with | | (E) with dimethylformamide and ROSiz, to obtain the compound of the formula (RK): (6) see (c) () combining the compound of formula (E) with a source of palladium and 4-chlorophenylboronic acid, in an organic solvent, to obtain the compound of formula (C): (c) () combining the compound of formula (Ci) with BOC-piperazine and sodium triacetoxyborohydride , in an organic solvent, to obtain the compound of the formula (H): Vos Y Z rez: ЧИ (Ну (К) combining the compound of the formula (H) with hydrochloric acid, to obtain the compound of the formula (1). 19. The method according to claim 18, where, at stage (i), the source of palladium is Pa(OAs)". 20. The method according to claim 18 or 19, where stage () includes combining tetrabutylammonium bromide with a compound of formula (E), a source of palladium and 4-chlorophenylboronic acid, in an organic solvent. 21. The method according to any one of claims 18-20, where stage (i) additionally includes obtaining the compound of formula (H) in the form of a crystalline solid. 22. The method according to any one of claims 18-21, where stage (K) additionally includes obtaining the compound of formula (I) in the form of a solid crystalline substance. 23. The method according to any one of claims 1-22, where A is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and neobutyl. 24. The method according to any one of claims 1-23, where AB means tert-butyl.